JPH0742231B2 - M1-Ophthalmic agents containing selective muscarinic pyridobenzodiazepinones - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to the regulation of eye development, and more specifically, to prevent the progression of myopia and / or
Or, it relates to ophthalmic treatment for prevention.

Myopia afflicts about 25% of the world population. In particular, myopia affects 15-75% of adolescents worldwide, depending on race, geographical distribution and degree of education. About half of all cases are classified as axial myopia, with the eyeball extending along the visual axis.

The human newborn eye is approximately 2 times the size of an adult eye.
/ 3. It is relatively short in the direction of the visual axis, i.e. in the axial direction. As a result, children are hypermetropic. As the length of the eyeball increases as the eye grows in childhood,
There are compensation mechanisms that govern structural changes in the cornea and lens. This process often works almost perfectly and does not require any correction to provide a sharp focus in the distance. However, when the accommodation mechanism goes wrong, the eye tends to be elongated in the visual axis direction. As a result, the distant image is focused before the plane of the retina and the patient has axial myopia.

Myopia is by no means a trivial maldevelopment of the eye. In the pathological state, the growth of the sclera (sclera) does not stop, the retina is pulled and degenerates, leading to permanent blindness. Surgical treatments to address this condition are often unsuccessful with rough cures.

Even in the milder class, myopia has been shown to affect the child's self-consciousness during important growth stages. Children wearing eyeglasses are tough, aggressive, and inactive, whether or not such an assessment is valid (Curtin, 1985). Because of this early childhood memory, parents with myopia often eagerly ask their doctors about treatments that stop the development of myopia when their child is diagnosed with myopia.

Furthermore, the optical correction means for myopia is not ideal and is dangerous. Approximate number 24 for the United States
There are 0 million contact lens wearers and is expected to double in the next five years. No matter how well matched and careful, complications associated with wearing contact lenses range from allergic reactions to permanent loss of vision due to corneal ulcers. In consideration of the importance of the latter problem, the Food and Drug Administration (FDA) has shortened the recommended wearing period from 30 days to "1 to 7 days" for contact lenses with long-wear specifications. In 1988, each hospital emergency room reported that more than 20,000 disorders related to contact lens wear were treated.

Although it is true that wearing spectacles eliminates most of the medical risks mentioned above, it is an acceptable option, as indicated by the person using the contact lens, despite the inconvenience of wearing contact lenses. is not. For this reason, great efforts have been made to correct myopia by corneal surgery using a conventional scalpel or excimer laser. However, all of these treatments are easy to revert to
Results are not predictable enough. Despite the risk of permanent visual impairment from these surgeries, thousands of people have undergone violent keratotomy in the United States.

Although optical and surgical correction of myopia corrects the refractive state of the eye, these procedures are not for abnormal eye growth during growth. Perkin
According to a 1982 s study, even low myopia with a refractive index of -1.00 to -5.00 predisposes to the development of glaucoma. People with myopia are more likely to suffer from retinal detachment because the retina is pulled and thinned. For this reason, there are some documents that list myopia as a risk factor of retinal detachment. All of the above highlights the need for drug therapies to address abnormal progression of myopia.

[0009]

2. Description of the Related Art The conventional therapeutic method based on drug administration has been the use of a ciliary muscle paralytic agent. Ciliary muscle paralytic agents are locally administered agents that relax the ciliary muscles, which are the muscles that control the size of the lens.

Atropine, which has been known as a belladonna alkaloid for over a century, is a classical ciliary muscle paralytic agent. Atropine is a long-lasting non-selective antimuscarinic agent that antagonizes the action of the chemical transmitter acetylcholine (ACh) in autonomic modulator cells stimulated by postganglionic cholinergic neurons of the parasympathetic nervous system.

In 1971, a two-year survey of Bedrossian's 75 myopia children was completed. In the first year, the right eye was treated by topical administration of 1.0% atropine at bedtime. The left eye was treated in the second year. As can be seen in Table 1, progression of myopia stopped in treated eyes. This result is significant at a risk rate of less than 1%.

Table 1 Effect of 1.0% atropine on myopia (Bedrossian, 1971) [Change in refraction indicated by refractive index, + is hyperopia, − is myopia] Right eye Left eye 1st year +0.20 -0.85 2nd year -1.05 + 0.17 Subsequent studies also confirmed the results of the first survey, showing that atropine exerts the maximum myopic slowing effect in children under 9 years of age (see Table 2).

Table 2 Progression of myopia (Brodstein, 1984) [Advance of refractive index every year, + is hyperopia, -is myopia] Age at the start of treatment 1.0% Atropine treatment Control <9 years -0.23 -0.69 9-12 Age -0.24 -0.48> 13 years -0.20 -0.23 Atropine, however, has not been widely used to delay myopia progression. The reason for this is phytotoxicity caused by dilated pupils, including glare, and obstruction of focus concentration, which is disadvantageous for near-view work such as reading. In addition to the discomfort experienced by patients, there is evidence that continued use of atropine or other long-term ciliary muscular paralytic agents should damage the retina when exposed to bright light.

Recently, selective acting antimuscarinic agents have been found to be effective in the treatment of myopia. This finding was made possible based on considerable evidence for newborns that links the posterior portion of the eye, specifically the imaging portion of the retina, the extension of the optic nervous system, with postnatal developmental eye development. . There is also significant evidence of myopia due to the eye that should be attributed to retinal image deterioration. In fact, both birds and primates,
It was shown that axial myopia was experimentally induced when the formed image was taken from the retina of the eye by stitching the eyelids and wearing spectacles that diverge the image. Experimental myopia induced in primates such as birds or monkeys approximates human normal axial myopia.

Thus, the process of forming visual acuity in an animal can be similar in appearance to a feedback mechanism based on normal regulation of postnatal eye growth and detection of refraction errors. This indicates that this mechanism is neural and likely to occur in the retina. According to RA Stone et al., It is possible to suppress the abnormal postnatal growth of the eyes of adult animals by regulating the existence of neurochemicals, agonists or antagonists of which are said to change during the maturation process associated with the abnormal visual axis. . In their article, the metabolism of certain retinal neurochemicals was altered in experimental animals such as chickens or monkeys that were exposed to visual image capture, which is usually associated with myopia development, and their retinal concentration was changed. Is disclosed to change. Specifically, during the visual deprivation period as described above, the retinal concentration of dopamine is decreased, and by instillation of a dopamine-related substance such as the dopamine agonist apomorphine, the axis of the eyeball even in a state that normally causes the above-mentioned elongation. It has been found that directional extension is hindered or virtually prevented.

There have been recent advances in understanding the cholinergic nervous system. Cholinergic receptors are cell wall-embedded proteins that respond to the chemical acetylcholine. These receptors are broadly classified into nicotinic and muscarinic receptors. In this regard, it is now known that muscarinic receptors are singular and not all. Recent findings indicate that there are at least five, if not more, muscarinic cholinergic receptors (types M ₁ to M ₅ ). Type M ₁ receptors are abundant and are thought to be abundant in cranial nerve tissues and ganglia. Other receptors are concentrated in other tissues such as the heart, smooth muscle tissue or glands. Although many drugs that interact with muscarinic receptors often affect several species, some have been found to have the main effect of showing relative selectivity for one type of receptor, others for others. It is possible to have a relative selection effect on one type of receptor. Still others may have a considerable effect on more than one, and possibly even all, receptors. For example, pirenzepine (gastrozepine, LS 519), 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,
[4] Benzodiazepin-6-one and its dihydrochloride are known to be anticholinergic, antimuscarinic and relatively M ₁ receptor selective. 4-DAMP (4-diphenylacetoxy-N-methylpiperazine methiodide) is also a relatively selective receptor for smooth muscle (common type M ₃
, But the classification of receptors is currently in a fluid state, and
₂ or M ₃ may be called differently). In contrast, atropine, mentioned above as a ciliary muscle paralytic agent, is a non-selective antagonist for all types of cholinergic muscarinic receptors.

Pirenzepine, which is mainly an M ₁ antagonist, inhibits axial elongation but is far inferior to atropine and other ciliary muscle paralytic agents in terms of pupil dilation. By utilizing this, it becomes possible to suppress the progression of myopia without enlarging the pupil and accommodating ciliary body encapsulation.

[0018]

However, pirenzepine has the following disadvantages. Local topical ocular administration of certain drugs to growing children is desirable with minimal ocular effects. In this respect, pirenzepine has a positive susceptibility test. This is the reason why there is a need for a selective antimuscarinic agent that can be used for myopia treatment and is less sensitive than pirenzepine without affecting the size of the pupil or the ciliary body inclusion.

[0019]

The present invention has the formula:

[0020]

[Chemical 7]

Myopia for preventing an abnormal increase in axial length of the eye, including a drug effective amount of the compound of the formula: wherein R is piperidine substituted with C _1-5 alkyl and a pharmaceutically acceptable salt thereof. It relates to a therapeutic drug. More specifically, the compound rispenzepine (urenzepine):

[0022]

[Chemical 8]

And nuvenzepine:

[0024]

[Chemical 9]

Can be used in the ophthalmic drug of the present invention which prevents an abnormal increase in the axial length of the eyeball and thus suppresses the progression of axial myopia.

The compounds of formula I are represented by the scheme:

[0027]

[Chemical 10]

According to the formula [wherein R is piperidine substituted with C _1-5 alkyl as described above], J. Med. Che
m. 6, 255, 1963; Bull.Soc.Chim.Fran. 7, 2316, 196
6; and as described in German Patent 1,179,943,
Starting from a compound of formula II, it is synthesized by acylation with an acid chloride of formula III. The reaction is carried out in a polar solvent such as dimethylformamide and dimethylsulfoxide in the presence of a base such as triethylamine, an alkali hydroxide and an alkali carbonate at a temperature from room temperature to 150 ° C and a reaction time of 2 to 24 hours. It

Representative pharmaceutically acceptable salts include, for example, the hydrochloride and maleate salts. The salt is generally synthesized as an acid addition salt by combining a nuclear compound and 1 to 3 equivalents of a suitable acid in an inert solvent. This salt evaporates the solvent, or when the salt spontaneously precipitates, it is filtered.
Alternatively, it is precipitated by the use of cosolvents or non-polar cosolvents, which are then recovered by filtration.

The term drug effective amount shall mean an amount of a drug or pharmaceutical agent that elicits a physiological or medical response of a tissue, system or organ desired by a veterinarian or doctor.

The term alkyl shall mean a straight-chain or branched alkane or alkene.

The term substitution is intended to include those substituted multiple times by the designated substituents.

[0033]

EXAMPLES The compounds used in the ophthalmic drug of the present invention can be easily prepared by using easily obtainable starting materials, reagents and conventional synthetic methods based on the examples described in detail below. . In these reactions, as known per se to the person skilled in the art, but not mentioned in detail here,
Variants can also be used. Additional technical background is taught in US Pat. No. 4,556,653, the entire disclosure of which is incorporated herein by reference.

Example 1 11- (1-Methylpiperidine-3-carbonyl) -5,11-dihydride
-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 1-methylpiperidine-3-carboxylic acid chloride hydrochloride (4.
7 g) to 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (5 g) and triethylamine (7.5 mL) in dimethylformamide (200 mL). Added to the solution. The reaction mixture was heated to 90 ° C. for 24 hr.

Example 2 11- (1-Methylpiperidine-4-carbonyl) -5,11-dihydride
-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one 1-methylpiperidine-4-carboxylic acid chloride hydrochloride (4.
7 g) to 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one (5 g) and triethylamine (7.5 mL) in dimethylformamide (200 mL). Added to the solution. The reaction mixture was heated to 90 ° C. for 24 hr.

The solvent was evaporated under reduced pressure and the residue was washed with 10% acetic acid (15
0 mL). This solution was repeatedly washed with methylene chloride, decolorized with activated carbon, and made alkaline to pH 8 with saturated aqueous sodium hydrogen carbonate. This was extracted with methylene chloride (5 x 100 mL). The organic extracts were combined, dried over sodium sulfate and evaporated. The residue was crystallized from ethanol / ethyl ether to give 11- (1-methylpiperidine-4-carbonyl) -5,11-dihydro-6H-pyrido [2,3-b] with a melting point of 265-267 ° C (decomposition).
[1,4] Benzodiazepin-6-one (2.4 g, yield 30%) was obtained.

The muscarinic agents used in the present invention are relatively selective for type M ₁ receptor inhibition and relatively inactive for type M ₃ smooth muscle receptors. The relative affinity for the M ₁ to M ₅ receptors is quantified by the test method described below.

Example 3 Three radioligand tests were performed in order to quantify the affinity of muscarinic antagonists for the M ₁ , M ₂ and M ₃ muscarinic receptor subtypes. M ₁ receptors in rat brain cortex are labeled with ³ H pirenzepine and M _{2 in} rat heart
The receptor is labeled with ³ H-AFDX-384 and the M ₃ receptor in the rabbit iris + ciliary body (subtracting ciliary processes containing the M ₁ receptor) is labeled with ³ H-QNB. Scatchard analysis labeled a population of binding sites in each tissue with the following Kd and Bmax values: cortex (2.36 nM, 164 f
mol / mg protein), heart (5.77 nM, 164 fmol / mg protein) and iris + cilia (24.5 pM, 210 fmol / mg protein). Ki values in a binding analysis of three kinds of atropine, rispenzepine, pirenzepine and nuvenzepine were determined. The most active drug at the M ₁ binding site was atropine, with a Ki value of 0.13 nM. Pirenzepine, nuvenzepine and rispenzepine had Ki values of 4.87 nM, 1.50 nM and 2.61 nM, respectively. Atropine is the most active M ₂ receptor antagonist with a Ki value of 0.82 nM, while pirenzepine (532 nM), nuvenzepine (248 nM) and rispenzepine (226 nM) are far inferior. . Atropine (0.37
nM) is also the most active at the M ₃ binding site,
Nubenzepine (29.7 nM), Pirenzepine (37.2 nM).
And rispenzepine (38.9 nM) follow. Atropine lacks substantial selectivity by the ability to discriminate between M ₁ and M ₃ receptors, with pirenzepine, nuvenzepine and rispenzepine being 8-fold, 20-fold and 15-fold, respectively.
Times, it is more selective for the M ₁ receptor than for the M ₃ receptor.

[0039]

[Table 1]

Alternatively, the absolute and relative affinities of the muscarinic antagonists at the M ₁ to M ₅ receptors can be determined by other methods known in the art. For a detailed description of techniques known to those of skill in the art for determining the binding capacity of five cloned human muscarinic receptors as antagonists, see, for example, Buckley et al., Molecular Pharmacolog.
y, 35: 469-476 (1989); Dorje et al., J. Pharmacol. Exp.T.
See hr. 256: 727-733 (1991). Similarly, M
₁ There are other ways to make functional studies that measure susceptibility. For example, the most popular method is to use the vas deferens of guinea pigs, which are susceptible to M ₁ . First, set so that the tension can be measured, and then the M ₁ agonist McNeil A
A known stimulant such as 343 is applied to change the tension by a known amount. Under this condition, the expected effect of the agonist is carefully plotted and then the extent to which each antagonist blocks the agonist effect is measured.

A myopic living animal model for screen purposes is obtained as follows.

Loss of myopia is induced in day-old White-leghorn chickens by aseptic anesthesia and suturing the eyelids of one eye. Place the chicken in a 12-hour light: dark cycle.
Sutured eyes were treated with nuvenzepine, rispenzepine and pirenzepine, and saline (control). The drug was injected subconjunctivally every day at light. The animals are sacrificed at the age of 2 weeks and the axial and equatorial dimensions of the unfixed eye are independently measured by two judges with vernier calipers. Rispenzepine and nuvenzepine have M ₁ compared to pirenzepine.
Due to its slightly higher activity at the receptor, it is expected to be at least as effective as pirenzepine in treating myopia.

Example 4 The US Food and Drug Administration requires a guinea pig maximization test for all drugs intended for eye drop administration. The test population for nuvenzepine and rispenzepine versus pirenzepine was at least 9 female Dunkin Hartley
Albino guinea pigs (300-500 g) were used with 10 control animals. In phase 1 which is the induction phase, generally the maximum tolerated concentration of the test substance (0.1 mL test substance in an equal volume mixture of Freund's complete adjuvant and distilled water) of the test substance was intradermally injected twice on the first day. To do. On day 7, 400 mg of a mixture of 10% sodium lauryl sulphate in petrolatum is prescribed in the shaving area. On day 8, 400 mg of the test compound in petrolatum was placed on a piece of 2 x 4 cm Whatman paper,
Formulate into the shaving inclusion area with Blenderm tape.

In the second phase, which is the challenging period, on the 22nd day
200 mg of petrolatum was applied to the shaved right flank, and the maximal unstimulated concentration of 200 mg of the test compound was applied to the shaved left flank micronized in petrolatum. Whichever the application,
I wrapped it up for 24 hours. Readings were taken on days 24 and 25, according to the following grades: 0 = no reaction, 1 = sporadic reddening, 2 = moderate reddening, 3 = intense reddening and swelling Nubenzepine and rispenzepine All showed 0, that is, there was no reaction in experimental animals. However, pirenzepine was grade 1 in 6 and grade 2 in 2 of the 9 total animals.

Diagnosis and treatment according to the present invention are well known to those skilled in the art.

The refractive condition of the eye can be easily known even with a newborn baby by using a handheld imager. This objective evaluation is carried out after ciliary muscle palsy in the eye obtained with topical administration of cyclopentolate or atropine. further,
The length measurement in the axial direction of the eyeball can be easily performed by ultrasonic examination.

Myopia becomes apparent when a child reaches the age of 7-12 years. Once that happens, myopia usually progresses until age 14 when development of the eye is complete.

Once it is diagnosed that myopia is developing, drug therapy can be initiated to slow the rate of progression. Treatment is continued until eye development is complete. For most children, treatment begins at the age of 7-10 years and ends at the age of 14 years.

Treatments that prevent axial elongation myopia during maturation can be prescribed using eye drops. In fact, in the majority of cases, therapeutic agents are given by eye drop application to the human eye. Eye drops typically contain the active ingredient in an ophthalmic vehicle.
It is formulated to contain a concentration of 0.5 to 2%. For clinical use, a 1% aqueous solution of rispenzepine or nuvenzepine is the appropriate concentration. In relation to pH or shelf life,
There are some restrictions on the formulation. A pH of about 6.5 seems to be acceptable as an ophthalmic ophthalmic solution and practical for the known solubility and stability of pyridobenzodiazepinones. Since pirenzepine is known to exhibit a strongly acidic solution in saline, it is recommended to treat it with a conventional compatible base to bring the pH to about 4.5 to 7.5 (preferably 6 or 6.5). Phosphate buffer is also commonly used for eye drops,
Compatible with rispenzepine and nuvenzepine. The usual manner of instillation is 2-3 times a day, evenly distributed during the wake-up period. The higher the potency of the drug, the less frequent dosing required or the use of more dilute solutions.

Alternatively, ointments and solid inserts are now being used more and more clinically. According to this, it is possible to avoid the problem of drug decomposition when delivering a predetermined amount of the drug. In the form of pills, capsules or other systemic formulations,
It is, of course, possible to formulate a pharmaceutically effective amount of the active ingredient.

In an animal experiment in which axial myopia is experimentally induced by depriving the retinal image, other experimentalists have found that amblyopia is also experimentally and simultaneously induced in primates. . Amblyopia is recognized as a loss of visual acuity in the eye, leading to inconvenience in visual activity. Normally, vision improves at maturity. The cause of amblyopia in humans is unknown and is known to occur as part of strabismus.

Of muscarinic antagonists, such as rispenzepine and nuvenzepine, which are relatively selective for M ₁ cholinergic receptor block and relatively non-selective for smooth muscle cell cholinergic receptor block. Administration of a pharmaceutically effective amount of the agent may prevent or inhibit permanent or persistent myopia in adult humans while avoiding the tendency associated with eye sensitization. Similar medical treatment with the above mentioned drugs may be able to save already developed persons with amblyopia due to other causes or even if the cause is unknown.

In addition to rispenzepine and nuvenzepine,
Other selective antimuscarinic pyridobenzodiazepinones within the scope of the present invention include:

N, N-Dimethyl-4-[[25,11-dihydro-6-oxo-6H-pyrido [2,3-b] [1,4] benzodiazepin-11-yl] carbonyl] piperidinium ioda Id

[0055]

[Chemical 11]

11-[(1-Ethylpiperidin-4-yl] carbonyl] -6,11-dihydro-5-oxo-5H-pyrido [1,2-b]
[1,5] benzodiazepines

[0057]

[Chemical 12]

Claims (6)

[Claims] 1. The formula: An ophthalmic agent for preventing an abnormal increase in the axial length of an eyeball in an animal, comprising a drug effective amount of the compound of the formula: wherein R is piperidine substituted with C _1-5 alkyl. 2. The formula: An ophthalmic agent for preventing an abnormal increase in the axial length of an eyeball in an animal, which comprises a drug effective amount of the compound of. 3. The formula: An ophthalmic agent for preventing an abnormal increase in the axial length of an eyeball in an animal, which comprises a drug effective amount of the compound of. 4. The formula: An ophthalmic agent for preventing progression of axial myopia in an animal, comprising a drug effective amount of the compound of the formula: wherein R is piperidine substituted with C _1-5 alkyl. 5. The formula: An ophthalmic agent for preventing the progression of axial myopia in an animal, which comprises a drug effective amount of the compound of. 6. The formula: An ophthalmic agent for preventing the progression of axial myopia in an animal, which comprises a drug effective amount of the compound of.